Placental Mosaicism Research Articles

Placental mosaicism and complications of pregnancy

Timely diagnosis of chromosomal aneuploidies plays an important role in determining the proper approach to the management of pregnancy. This article outlines the current ideas on the likelihood of occurrence of obstetric pathology, depending on the number of cells with genetic aberration, especially in the placenta. Such obstetric complications include fetal growth retardation, premature birth, and some forms of preeclampsia. The article describes the prenatal examination techniques, which help obtain timely information about the development of the fetus and predict pregnancy complications, more specifically, non-invasive prenatal DNA screening as a new technique with its advantages and limitations, based on the analysis of DNA of placental origin. It also highlights other latest diagnostic tools that allow to get more accurate information about placental mosaicism and the development of pathology. We have reviewed publications over the past 10 years, which are devoted to the factors responsible for the formation of placental mosaicism, the prenatal diagnostic procedures required for an accurate diagnosis, and the likelihood of obstetric pathology in case of prolonged pregnancy complicated by genetic aberrations. Foreign studies confirm the direct dependence of the likelihood of obstetric pathology on the number of cells with genetic aber ration. In accordance with the above study results, it would be only right to note that placental insufficiency can be observed in any case of genetic aberration, especially if a large volume of cells is involved in the pathological process at an early stage of differentiation. In addition, the article discusses the issue of need of thorough prenatal diagnosis to prevent the development of pregnancy pathology, including the use of the latest technologies and minimizing invasive methods.

Reply: The missing role of diagnosis of confined placental mosaicism in the management of fetal growth restriction.

Reply: The missing role of diagnosis of confined placental mosaicism in the management of fetal growth restriction.

The missing role of diagnosis of confined placental mosaicism in the management of fetal growth restriction.

The missing role of diagnosis of confined placental mosaicism in the management of fetal growth restriction.

Clinical Validation of Fetal cfDNA Analysis Using Rolling-Circle-Replication and Imaging Technology in Osaka (CRITO Study).

Background: Noninvasive prenatal genetic testing (NIPT) has been adopted as the first choice for aneuploidy screening. The purposes of this study were to investigate the accuracy of Vanadis® NIPT (hereafter CRITO-NIPT) in order to gain a deeper insight into the reasons for discrepancies, as well as to discuss the role of fetal ultrasound. Methods: Between 2019 and 2020, CRITO-NIPT was performed in 1218 cases of patients who underwent CVS or amniocentesis after a detailed fetal ultrasound exam and genetic counseling. The CRITO-NIPT results were compared with the genetic results. In cases of test discrepancies, the placentae were collected for detailed genetic research, and the pre-procedure fetal ultrasound findings were referred to. Results: The positive predictive value of T21, T18, and T13 was 93.55%, 88.46%, and 100%, respectively. In 90% of the of false positive (FP) cases, the placentae were examined. In 75% of the CRITO FP-T21 cases, placental mosaicism, or a demised twin’s T21, were confirmed. There were complicated mosaic cases, including tetrasomy 21/trisomy7 and monosomy 21/trisomy21 cases. In one of three no-call cases, an intermediate deletion of chromosome 13 was detected. Conclusions: The CRITO study investigated the mechanism of false positives, and the detailed mechanisms in mosaic and no-call cases. There have hitherto been no reports that have provided insight by partitioning the placenta to compare the NIPT and invasive test results, nor that have provided detailed ultrasound findings in the cases of discordant results, revealing the demonstrated importance of, and necessity for, detailed ultrasonography. This article describes the potential of rolling-circle replication as a powerful biosensing platform, as well as the importance of examining the fetus in detail with ultrasound. However, we should remember that the potential applications raise ethical and social concerns that go beyond aneuploidy and its methodology.

VP36.02: Rate of confined placental mosaicism assessed after delivery of normal euploid neonates with or without SGA: a systematic review and meta‐analysis

VP36.02: Rate of confined placental mosaicism assessed after delivery of normal euploid neonates with or without SGA: a systematic review and meta‐analysis

VP28.07: Impact of confined placental mosaicism on outcome of pregnancy

To assess the incidence of confined placental mosaicism (CPM) on CVS and amniocentesis in our population and to study the impact of CPM on the outcome of pregnancies with a structurally normal fetus at mid trimester anomaly scan and the association of abnormal first trimester serum biochemistry with CPM. This is a single centre study where all pregnancies that had an invasive procedure ie CVS or amniocentesis before 20 weeks of gestation from January 2011 till December 2020 were considered. The study included pregnancies that had mosaic pattern on CVS or amniocentesis. The incidence of CPM on CVS and amniocentesis was calculated. Fetal ultrasound in all trimesters, maternal serum biochemistry in the first trimester, presence of fetal growth restriction (FGR) and postnatal outcome were obtained. During the study period, of the 2081 Amniocentesis procedures 1 (0.05%) had CPM with tetraploidy mosaic confirmed by postnatal karyotype with normal outcome. Of 1144 CVS procedures performed 10/1144 (0.9%) were detected to have a mosaic pattern. 5/10 mosaic pattern obtained in pregnancies with fetal structural abnormalities were terminated before amniocentesis could be performed. 5/10 (0.44%) had structurally normal fetuses and hence Amniocentesis could be performed to confirm CPM. Of the four where first trimester serum biochemistry was available, three (75%) cases had low maternal serum PAPP-A (< 0.3). 2 of 5 cases had Trisomy 18, one had Trisomy 16 and one had Trisomy 21 mosaic pattern, all of which had normal antenatal and postnatal outcomes. 1/5 pregnancies had Trisomy 16 mosaic pattern which was found to have severe early onset FGR at 18 weeks and was terminated. Hence, 1/5 pregnancies with CPM had poor fetal outcome. The incidence of CPM in our study was about 0.44% on CVS and that on amniocentesis 0.05%. FGR was the only antenatal complication. We did not observe any maternal complications. Low maternal serum PAPP-A levels may indicate a higher possibility of obtaining a mosaic pattern on a CVS.

Outcomes of pregnancies with trisomy 16 mosaicism detected by NIPT: a series of case reports

BackgroundTrisomy 16 (T16) is thought to be the most frequent chromosome abnormality at conception, which is often associated with a high risk of abnormal outcomes.MethodsA retrospective analysis of 14 cases with high risk of T16 by noninvasive prenatal testing (NIPT) was conducted. All cases in the analysis involved prenatal diagnosis, karyotyping and chromosomal microarray analysis.Case reportsNIPT detected 12 cases of T16 and 2 cases of T16 mosaicism. Prenatal diagnosis confirmed 5 true positive cases and 9 false positive cases. Among the 5 true positive cases, 3 cases had ultrasound abnormalities. All of the 9 false positive cases continued their pregnancies. The newborns who were from these 9 false positive cases except 1 case (case 7) had low birth weights (< 2.5 kg) and there were also 2 premature deliveries.ConclusionNIPT serves as a fast and early prenatal screening method, giving clues to chromosome abnormalities and providing guidance for managing pregnancy. Confined placental mosaicism in 16 pregnancies may be at higher risk for preterm delivery.

Inherent mosaicism and extensive mutation of human placentas

Placentas can exhibit chromosomal aberrations that are absent from the fetus1. The basis of this genetic segregation, which is known as confined placental mosaicism, remains unknown. Here we investigated the phylogeny of human placental cells as reconstructed from somatic mutations, using whole-genome sequencing of 86 bulk placental samples (with a median weight of 28 mg) and of 106 microdissections of placental tissue. We found that every bulk placental sample represents a clonal expansion that is genetically distinct, and exhibits a genomic landscape akin to that of childhood cancer in terms of mutation burden and mutational imprints. To our knowledge, unlike any other healthy human tissue studied so far, the placental genomes often contained changes in copy number. We reconstructed phylogenetic relationships between tissues from the same pregnancy, which revealed that developmental bottlenecks genetically isolate placental tissues by separating trophectodermal lineages from lineages derived from the inner cell mass. Notably, there were some cases with full segregation—within a few cell divisions of the zygote—of placental lineages and lineages derived from the inner cell mass. Such early embryonic bottlenecks may enable the normalization of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue. Our findings reveal extensive mutagenesis in placental tissues and suggest that mosaicism is a typical feature of placental development. Phylogenies of human placental cells based on whole-genome sequencing of bulk samples and microdissections reveal extensive mutagenesis in placental tissue, and suggest that mosaicism is a typical part of normal placental development.

Diagnostic testing after positive results on cell free DNA screening: CVS or Amnio?

The positive predictive values of cell free DNA (cfDNA) and rates of confined placental mosaicism (CPM), imprinting and other factors vary by chromosome. We sought to review the literature for each of these features for each chromosome and provide recommendations on chorionic villus sampling (CVS) versus amniocentesis after an abnormal cfDNA result. For chromosomes with high rates of CPM (trisomy 13, monosomy X and rare autosomal trisomies [RATs]), an amniocentesis should be considered if the first trimester ultrasound is normal. For monosomy X on cfDNA with an unaffected fetus, maternal karyotyping should be considered after normal fetal diagnostic testing. In cfDNA cases with a trisomy involving a chromosome with imprinted genes (6, 7, 11, 14, 15 and 20), CVS should be considered, followed by amniocentesis if abnormal. If the fetus is unaffected, methylation studies should be considered given the risk of uniparental disomy. A third trimester growth ultrasound should be considered for patients with a positive cfDNA screen for a RAT and an unaffected fetus, especially in the case of trisomy 16. For patients with multiple aneuploidy results on cfDNA, a work-up for maternal malignancy should be considered. Clinicians should consider rates of CPM, imprinting, ultrasound findings and maternal factors when considering whether to recommend amniocentesis or CVS after an abnormal cfDNA result.

Prenatal Diagnosis of True Fetal Mosaicism with Small Supernumerary Marker Chromosome Derived from Chromosome 16 by Funipuncture and Molecular Cytogenetics Including Chromosome Microarray

This study examined the molecular characterization of a prenatal case with true fetal mosaicism of small supernumerary marker chromosome 16 (sSMC(16)). A 41-year-old female underwent amniocentesis at 19 weeks of gestation due to advanced maternal age. Chromosomal analysis for cultured amniocytes revealed a karyotype of 47,XY,+mar[4]/46,XY[16]. Spectral karyotyping and metaphase fluorescence in situ hybridization (FISH) demonstrated that the sSMC was derived from chromosome 16 (47,XY,+mar.ish der(16)(D16Z1+)[13/20]). Confined placental mosaicism was initially suspected because the prenatal ultrasound revealed a normal structure and the pregnancy was uneventful. However, interphase FISH of cord blood performed at 28 weeks of gestation showed 20% mosaicism of trisomy chromosome 16 (nuc ish(D16Z2×3)[40/200]). Chromosome microarray analysis further demonstrated 55% mosaicism of an 8.02 Mb segmental duplication at the subcentromeric region of 16p12.1p11.1 (arr[GRCh37] 16p12.1p11.1(27021975_35045499)×3[0.55]). The results demonstrated a true fetal mosaicism of sSMC(16) involving chromosome16p12.1p11.1 that is associated with chromosome 16p11.2 duplication syndrome (OMIM #614671). After non-directive genetic counseling, the couple opted for late termination of pregnancy. This case illustrated the use of multiple molecular cytogenetic tools to elucidate the origin and structure of sSMC, which is crucial for prenatal counseling, decision making, and clinical management.

Discordant structural chromosomal aberrations in chorionic villi and amniotic fluid leading to a formation of an isochromosome 21: a case report

BackgroundFetoplacental discrepancies occur in approximately 1–2% of analyzed prenatal cases. They are typically due to confined placental mosaicism, where an aberration is observed in the placental cells but not found in the fetal cells. Confined placental mosaicism usually involves aneuploidies and more sparsely structural chromosomal aberrations. To the best of our knowledge, this is the first reported case of a discrepancy in the analyses of chorionic villus sampling and amniocentesis involving two different structural chromosomal aberrations of chromosome 21.Case presentationWe report a 33-year-old woman who was referred for a non-invasive prenatal testing due to an increased risk of trisomy 21 gleaned from a combined ultrasound and blood test. The non-invasive prenatal testing showed an increased risk of trisomy 21 with a normalized coverage signal that did not match the fetal cell-free DNA fraction. Rapid aneuploidy detection performed on uncultured chorionic villi indicated mosaicism for trisomy 21. The follow-up analyses revealed discordant chromosomal aberrations: 46,XY,der(21)t(10;21)(p11.21;q10) in the analysis of the chorionic villus sampling and 46,XY, + 21,der(21;21)(q10;q10) in the analysis of the amniocentesis. Thus, the analyses indicated mosaicism for a cell line containing trisomy 21 and a cell line containing a partially duplicated short arm of chromosome 10 in the chorionic villi and complete trisomy 21 resulting from an isochromosome 21 in the amniotic fluid. The analyses of the lymphocytes and the fibroblasts of the woman were normal.ConclusionsWe propose a multiple-step mechanism as a possible theoretical explanation for the formation of these discordant structural chromosomal aberrations in the chorionic villi and amniotic fluid. With this case report, we want to highlight the importance of understanding the possible underlying embryological mechanisms when interpreting results from different prenatal analyses.

Confined placental mosaicism and the association with pregnancy outcome and fetal growth: a review of the literature.

BACKGROUNDChromosomal mosaicism can be detected in different stages of early life: in cleavage stage embryos, in blastocysts and biopsied cells from blastocysts during preimplantation genetic testing for aneuploidies (PGT-A) and later during prenatal testing, as well as after birth in cord blood. Mosaicism at all different stages can be associated with adverse pregnancy outcomes. There is an onward discussion about whether blastocysts diagnosed as chromosomally mosaic by PGT-A should be considered safe for transfer. An accurate diagnosis of mosaicism remains technically challenging and the fate of abnormal cells within an embryo remains largely unknown. However, if aneuploid cells persist in the extraembryonic tissues, they can give rise to confined placental mosaicism (CPM). Non-invasive prenatal testing (NIPT) uses cell-free (cf) DNA released from the placenta in maternal blood, facilitating the detection of CPM. In literature, conflicting evidence is found about whether CPM is associated with fetal growth restriction (FGR) and/or other pregnancy outcomes. This makes counselling for patients by clinicians challenging and more knowledge is needed for clinical decision and policy making.OBJECTIVE AND RATIONALEThe objective of this review is to evaluate the association between CPM and prenatal growth and adverse pregnancy outcomes. All relevant literature has been reviewed in order to achieve an overview on merged results exploring the relation between CPM and FGR and other adverse pregnancy outcomes.SEARCH METHODSThe following Medical Subject Headings (MESH) terms and all their synonyms were used: placental, trophoblast, cytotrophoblast, mosaicism, trisomy, fetal growth, birth weight, small for gestational age and fetal development. A search in Embase, PubMed, Medline Ovid, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar databases was conducted. Relevant articles published until 16 July 2020 were critically analyzed and discussed.OUTCOMESThere were 823 articles found and screened based on their title/abstract. From these, 213 articles were selected and full text versions were obtained for a second selection, after which 70 publications were included and 328 cases (fetuses) were analyzed. For CPM in eight different chromosomes (of the total 14 analyzed), there was sufficient evidence that birth weight was often below the 5th percentile of fetal growth standards. FGR was reported in 71.7% of CPM cases and preterm birth (<37 weeks of delivery) was reported in 31.0% of cases. A high rate of structural fetal anomalies, 24.2%, in cases with CPM was also identified. High levels of mosaicism in CVS and presence of uniparental disomy (UPD) were significantly associated with adverse pregnancy outcomes.WIDER IMPLICATIONSBased on the literature, the advice to clinicians is to monitor fetal growth intensively from first trimester onwards in case of CPM, especially when chromosome 2, 3, 7, 13, 15, 16 and 22 are involved. In addition to this, it is advised to examine the fetuses thoroughly for structural fetal anomalies and raise awareness of a higher chance of (possibly extreme) premature birth. Despite prematurity in nearly a fifth of cases, the long-term follow-up of CPM life borns seems to be positive. More understanding of the biological mechanisms behind CPM will help in prioritizing embryos for transfer after the detection of mosaicism in embryos through PGT-A.

Mosaicism for copy number variations in the placenta is even more difficult to interpret than mosaicism for whole chromosome aneuploidy.

To compare mosaicisms in prenatal chorionic villus samples (CVSs) with corresponding postpartum placental samples. We collected placentas from 15 consecutive cases of mosaicism detected in CVSs and obtained five standardized samples on each placenta after delivery. All pre- and postnatal placental samples were uncultured and analyzed by high-resolution chromosomal microarray. Ten cases of mosaicism for whole chromosome aneuploidy (mWC) and five cases with mosaicism for (sub)chromosomal copy number variations (mCNVs) were included. In 5/10 mWC cases and in 4/5 mCNV cases the prenatally detected aberration was confirmed in the postpartum placenta. Three postpartum placentas revealed various complex aberrations differing from the prenatal results: (1) mosaicisms for different deletions/duplications on 9p and 9q in all samples (prenatal: mosaic 5.3Mb duplication on 9p24), (2) different regions with deletions/duplications/loss of heterozygosity on 1p in all samples (prenatal: mosaic 2.3Mb 1p36 duplication), and (3) mosaicism for a duplication on 5q and a deletion on 6p in one out of five samples (prenatal: mosaic trisomy 7). CNVs constitute a complex subgroup in placental mosaicism. Counseling of these couples after chorionic villus sampling should not focus on the specific CNV involved, but on the nature of mosaicism and the option of amniocentesis and ultrasound.

Impact of confined placental mosaicism on non-invasive prenatal testing and pregnancy outcomes

To assess the impact of confined placental mosaicism (CPM) on non-invasive prenatal testing (NIPT) and pregnancy outcomes. Copy number variation sequencing (CNV-seq) and single nucleotide polymorphism array (SNP-array) were carried out on placental specimen sampled from eight pregnancies with confirmed false-positive NIPT results. The impact of CPM on NIPT and pregnancy outcomes were analyzed based on the laboratory tests and clinical characteristics. Five of the eight cases with false-positive NIPT results were proven to be CPM involving trisomy 9, 13, 21, 22, and X, respectively. The mosaic ratios for different placental regions have varied from 4% to 80%. Two fetuses with confirmed CPM showed fetal growth restriction (FGR) and additional ultrasound abnormalities, 1 fetus showed only FGR. The remaining two fetuses showed normal growth. NIPT is highly sensitive to CPM, whilst CPM is an important cause for false-positive NIPT result. CPM may be associated with FGR. Investigation of the presence of CPM is important for both pre- and post-test genetic counseling and management of the pregnancy.

Inherent mosaicism and extensive mutation of human placentas.

Placentas can exhibit chromosomal aberrations that are absent from the fetus1. The basis of this genetic segregation, which is known as confined placental mosaicism, remains unknown. Here we investigated the phylogeny of human placental cells as reconstructed from somatic mutations, using whole-genome sequencing of 86bulk placental samples (with a median weight of 28mg) and of 106microdissections of placental tissue. We found that every bulk placental sample represents a clonal expansion that is genetically distinct, and exhibits a genomic landscape akin to that of childhood cancer in terms of mutation burden and mutational imprints. To our knowledge, unlike any other healthy human tissue studied so far, the placental genomes often contained changes in copy number. We reconstructed phylogenetic relationships between tissues from the same pregnancy, which revealed that developmental bottlenecks genetically isolate placental tissues by separating trophectodermal lineages from lineages derived from the inner cell mass. Notably, there were some cases with full segregation-within a few cell divisions of the zygote-of placental lineages and lineages derived from the inner cell mass. Such early embryonic bottlenecks may enable the normalization of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue. Our findings reveal extensive mutagenesis in placental tissues and suggest that mosaicism is a typical feature of placental development.

356 Is placental mosaicism identified by CVS associated with higher rates of adverse obstetric outcomes?

Placental mosaicism is identified in approximately 1-2% of women who undergo CVS. While high rates of adverse obstetric outcomes have been described, data is inconsistent. Our objective was to compare outcomes in pregnancies with and without mosaicism identified at CVS. All women who underwent CVS followed by amniocentesis from 2010-2020 were identified. Those who underwent amniocentesis due to mosaicism on CVS were compared to those who underwent amniocentesis after CVS for other reasons. Pregnancies terminated for genetic abnormalities were excluded. Obstetric outcomes were compared between the two groups. Student t test and Fisher’s exact test were used for statistical comparison. During the study period 2539 women underwent CVS, and 66 (2.6%) subsequently underwent amniocentesis: 29 (44%) due to mosaicism, 22 (33%) due to sampling/laboratory issues, and 15 (23%) for additional diagnostic testing. The most common forms of mosaicism were for sex chromosome abnormalities (n=4), tetraploidy (n=4), and Trisomy 9 (n=4). Mean maternal age was 36.7 ± 3.5-yrs, and 41% of women were nulliparous. Age and parity were similar between groups. There were no pregnancy losses or stillbirths. Obstetric outcomes are in Table 1. Those who had placental mosaicism did not have higher rates of adverse outcomes compared to those who underwent amniocentesis following CVS due to other reasons. Placental pathology was performed in 41% of cases, and placental mosaicism was not associated with higher rates of lesions of malperfusion (45.5% vs. 37.5%, p=0.71). We did not observe an association between placental mosaicism and adverse obstetric outcomes. As our study cohort consisted of small numbers of different forms of mosaicism, it is unclear if specific mosaic karyotypes have higher rates of adverse outcomes.

168 Non invasive prenatal testing and ultrasound fetal sex discrepancy: what are we missing?

Non invasive prenatal testing (NIPT) for fetal sex chromosomes has a sensitivity of 99%. However, discordant fetal sex results on NIPT and anatomical ultrasound (US) have been reported at a rate of 0.0-0.9%. These results are commonly attributed to sampling errors, a vanishing twin, placental mosaicism, or disorders of sexual differentiation. The aim of this study was to identify additional genetic causes of this discordance. This was a retrospective observational study from 8/2015 -1/2020. A database was queried to identify discordance between fetal sex reported on NIPT and the observed genital phenotype on US. Pregnancies with anomalies and ongoing multifetal gestations were excluded. The NIPT brand, fetal fraction, invasive testing results, and pregnancy outcomes were reviewed. Twenty seven cases of discordance were identified, representing 0.2% of patients. NIPT was normal in 24 cases, and 45X was predicted in 3. Cases were classified into 5 categories (Table 1). Invasive testing was performed in 13 cases, with abnormal genotypes identified in 7 cases, including abnormal karyotypes in all 3 cases with NIPT consistent with 45X and male genitalia (Table 2). In 5 cases, the patient chose pregnancy termination. In cases with normal NIPT and discordant genitalia, invasive testing identified abnormal genotypes in 4 cases, with karyotype consistent with US in the remaining 6 cases. In 14 cases without invasive testing, 7 had normal anatomy at birth, with genitalia consistent with US. Five of these cases were likely secondary to “vanishing twin” based on early US demonstrating an additional non-viable gestation. In 2 cases without invasive testing, ambiguous genitalia was noted at birth, with presumptive diagnoses of partial androgen insensitivity. In most pregnancies with normal NIPT results and phenotypically normal appearing but discordant genitalia, the genotype is consistent with phenotype. However, some have genetic abnormalities. All pregnancies with discordant NIPT/US results should be offered invasive testing to inform counseling and pregnancy management.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Noninvasive Prenatal Testing as Compared to Chorionic Villus Sampling Is More Sensitive for the Detection of Confined Placental Mosaicism Involving the Cytotrophoblast

(Abstracted from Prenat Diagn 2020;40:1338–1342) Confined placental mosaicism (CPM) describes a chromosomally abnormal placenta with a chromosomally normal fetus. Confined prenatal mosaicism may be detected prenatally by either chorionic villus sampling (CVS) or noninvasive prenatal testing (NIPT) using cell-free DNA (cfDNA), which evaluates the DNA released from cytotrophoblast (CTB) into maternal blood.

Clinical Practice Guidelines for Prenatal Aneuploidy Screening and Diagnostic Testing from Korean Society of Maternal-Fetal Medicine: (2) Invasive Diagnostic Testing for Fetal Chromosomal Abnormalities.

The Korean Society of Maternal Fetal Medicine proposed the first Korean guideline on prenatal aneuploidy screening and diagnostic testing, in April 2019. The clinical practice guideline (CPG) was developed for Korean women using an adaptation process based on good-quality practice guidelines, previously developed in other countries, on prenatal screening and invasive diagnostic testing for fetal chromosome abnormalities. We reviewed current guidelines and developed a Korean CPG on invasive diagnostic testing for fetal chromosome abnormalities according to the adaptation process. Recommendations for selected 11 key questions are: 1) Considering the increased risk of fetal loss in invasive prenatal diagnostic testing for fetal genetic disorders, it is not recommended for all pregnant women aged over 35 years. 2) Because early amniocentesis performed before 14 weeks of pregnancy increases the risk of fetal loss and malformation, chorionic villus sampling (CVS) is recommended for pregnant women who will undergo invasive prenatal diagnostic testing for fetal genetic disorders in the first trimester of pregnancy. However, CVS before 9 weeks of pregnancy also increases the risk of fetal loss and deformity. Thus, CVS is recommended after 9 weeks of pregnancy. 3) Amniocentesis is recommended to distinguish true fetal mosaicism from confined placental mosaicism. 4) Anti-immunoglobulin should be administered within 72 hours after the invasive diagnostic testing. 5) Since there is a high risk of vertical transmission, an invasive prenatal diagnostic testing is recommended according to the clinician's discretion with consideration of the condition of the pregnant woman. 6) The use of antibiotics is not recommended before or after an invasive diagnostic testing. 7) The chromosomal microarray test as an alternative to the conventional cytogenetic test is not recommended for all pregnant women who will undergo an invasive diagnostic testing. 8) Amniocentesis before 14 weeks of gestation is not recommended because it increases the risk of fetal loss and malformation. 9) CVS before 9 weeks of gestation is not recommended because it increases the risk of fetal loss and malformation. 10) Although the risk of fetal loss associated with invasive prenatal diagnostic testing (amniocentesis and CVS) may vary based on the proficiency of the operator, the risk of fetal loss due to invasive prenatal diagnostic testing is higher in twin pregnancies than in singleton pregnancies. 11) When a monochorionic twin is identified in early pregnancy and the growth and structure of both fetuses are consistent, an invasive prenatal diagnostic testing can be performed on one fetus alone. However, an invasive prenatal diagnostic testing is recommended for each fetus in cases of pregnancy conceived via in vitro fertilization, or in cases in which the growth of both fetuses differs, or in those in which at least one fetus has a structural abnormality. The guidelines were established and approved by the Korean Academy of Medical Sciences. This guideline is revised and presented every 5 years.

Trisomy 8 mosaicism in the placenta: A Danish cohort study of 37 cases and a literature review.

To evaluate the risk of fetal involvement when trisomy 8 mosaicism (T8M) is detected in chorionic villus samples (CVS). A retrospective descriptive study of registered pregnancies in Denmark with T8M in CVS identified through a database search and a review of published cases of T8M found through a systematic literature search and inclusion of cross references. Pregnancies with T8M in CVS and no additional numerical chromosomal aberrations were included. A total of 37 Danish cases and 60 published cases were included. T8M detected in a CVS was associated with fetal involvement in 18 out of 97 pregnancies (18.6% [95%CI: 11.4-27.7]). Eight out of 70 (11.4% [95%CI: 5.1-21.3]) interpreted prenatally to be confined placental mosaicism (CPM) were subsequently found to be true fetal mosaicisms (TFM). T8M detected in CVS poses a significant risk of fetal involvement, and examination of amniotic fluid (AF) and/or fetal tissue should be offered. However, a normal result of AF still has a considerable residual risk of fetal involvement. Genetic counselling at an early gestational age is essential, and follow-up ultrasonography should be performed to predict fetal involvement if possible.